The goal of this project is to characterize the role of neurotrophins (NTs), and associated signal transduction pathways, in developing and regenerating olfactory receptor neurons (ORNs). NTs and their cognate receptors, Trk A, Trk B, an Trk C, are crucial to many aspects of neuronal development. However, their low endogenous levels of expression in vivo and in primary cultures have made elucidation of NT signaling cascades and cross-talk with stimulus-driven-cascades difficult. ORNs express high levels of Trk receptors, facilitating analysis of NT signaling cascades. Our data also demonstrate that the NT and odorant-activated cascades interact. This project has two Specific Aims. [I] To determine the role of NTs during ORN development and regeneration. I will characterize morphological changes in the olfactory system in mice null for BDNF and NT-3 (alone or in combination), and determine NT and Trk receptor expression in several regenerative paradigms. [2] To study NTs signal transduction and cross-talk with odorant-induced cascades using primary cultures of ORNs. These experiments will provide insight into the specific roles and BDNF and NT-3 and their associated signal transduction mechanisms in neuronal development.